Many pharmacologically active agents cannot be effectively administered by the oral route because of poor systemic absorption from the gastrointestinal tract. Therefore, these agents are generally administered via the intravenous or intramuscular routes. This requires hospitalization or care by a health professional, entailing discomfort, potential trauma to the patient and even added cost. Other pharmacologically active agents may be administered by the oral route, but a combination of poor absorption and/or rapid breakdown during the first pass through the liver, requires large and toxic doses to achieve therapeutic concentrations systemically.
Methods disclosed in the art for increasing gut absorption of drugs focus on the use of solubility and permeation enhancers as promoting agents. But the above methods suffer from numerous drawbacks. The solubility and permeability enhancers are often ineffective for oral administration in the doses required and may interfere with pharmacological activity of the target drug. Some even cause clinical consequences, for example, intravenous administration of quinidine may cause arrhythmias, peripheral vasodilation, upset gastrointestinal function and the like.
Difficulties continue to exist in delivery systems for water-insoluble pharmaceutical agents despite the development of techniques using lipid vesicles and oil-in-water type of emulsions. However, these formulations require presence of solvents such as dimethyl sulfoxide or polyethylene glycol that cause physical instability in the formulation. Ogawa et al., U.S. Pat. No. 5,004,756; Tabibi et al., U.S. Pat. No. 5,039,527; and Carter, U.S. Pat. No. 5,461,037.
U.S. Pat. No. 6,838,090 claims a vesicular drug delivery system which comprises a drug solution comprising a water-insoluble drug, dissolved in a pharmaceutically acceptable water miscible organic solvent, and a surfactant suspension comprising water and 0.5% to 10% (w/v) of a surfactant wherein the surfactant forms vesicles having an average particle size from 50 nm to 200 nm, wherein the drug solution and surfactant suspension are stored and transported separately, and combined prior to use. The water-insoluble drugs included antihypertension drugs, antibiotics, anticancer or antitumor drugs, and specifically selected from the group consisting of 17-allylaminogeldanamycin and carboxyamidotriazole (CAI). The water-miscible organic solvent was selected from the group consisting of dimethyl formamide, ethanol, glycerine, propylene glycol, polyethylene glycol, dimethyl sulfoxide and dimethyl acetamide.
With the advent of nanotechnology, drug delivery systems have improved but the side effects and toxicity profiles of the drugs have remained unchanged.
It is well known that a series of membrane-bound P-glycoproteins function as energy-dependent transport or efflux pumps to prevent certain pharmaceutical compounds from traversing the mucosal cells of the small intestine and, therefore from being absorbed into the systemic circulation. A number of non-cytotoxic pharmacological agents have been shown to inhibit P-glycoprotein, including cyclosporine, verapamil, tamoxifen, quinidine and phenothiazines, among others. Many of these studies were conducted to achieve greater accumulation of cytotoxic drugs inside tumor cells, for example, the effects of cyclosporine were studied on the pharmacokinetics and toxicities of paclitaxel, doxorubicin and etoposide (Sugiyama et al Biochem Biophys Acta 1653: 47-59 (2003); Malingre et al., J. Clin Oncol 19: 1160-1166 (2001)). All of these drugs are anti-cancer agents known to be subject to multidrug resistance (MDR). These studies indicated that concomitant administration of cyclosporine suppressed the MDR action of P-glycoprotein and resulted in larger intracellular accumulations of the therapeutic agents.
Another approach taken to modulate the pharmacological profile of a drug is to inhibit or prevent its metabolism. Carboxyamidotraiazole (CAI) is a novel neoplastic agent in clinical development with limited oral bioavailability (Bauer et al, Clinical Cancer Research 5:2324-2329, (1999). Since in vitro, ketoconazole has been demonstrated to inhibit CYP3A4 mediated metabolism of CAI, a phase I trial in forty seven patients was undertaken in which CAI and ketoconazole were co-administered. There was an increase in the area under curve (AUC) and Cmax with a decrease in CAI clearance compared to the control. However, the toxicity profile of CAI was not altered (Desai et al, Cancer Chemotherapy Pharmacology 54: 377-384, (2004).
Carboxyamidotriazole (CAI) is currently under development for clinical use as an antitumor agent based on its antiangiogenic, antiproliferative and antimetastatic effects Kohn et al Cancer Res 52: 3208-3212, (1992); Bauer et al J. Pharm Exp Ther 292: 31-37 (2000) and Purow et al, Cancer Investigation 22: 577-587, (2004).
U.S. Pat. No. 5,861,406 issued on Jan. 19, 1999 and U.S. Pat. No. 5,912,346 issued on Jul. 15, 1999, describe treatment and prevention of neoplasms with salts of aminoimizazole carboxamide and CAI triazole. Specifically, an orotate salt of CAI compared with CAI, was found to have improved antitumor effect in the Dunning rat model for prostate cancer. The mechanism of action for the enhancement in antitumor activity of CAI orotate was not described but was suggested to involve an alteration in cyclic nucleotide activity in the liver.
At most pharmaceutical companies, while many technologies such as combinatorial chemistry, nanotechnology, rapid analog synthesis, automated synthesis open access liquid chromatography mass spectrometry, and high-speed automated high-performance liquid chromatography are now affecting medicinal chemistry, their main effect has been to shorten the cycle time of synthetic operations. One of the most difficult properties to build into a newly discovered lead molecule is the desired pharmacokinetic profile, particularly in the case of orally dosed compounds. “Most experienced medicinal chemists would prefer to start in a structural series that has inherently good pharmacokinetic properties, albeit with poor potency on the target receptor, and then set about improving the potency on the target, rather than working in the other direction”, “Organic Chemistry in Drug Discovery, Drug Discovery”, Science 303: 1810-1813 (2004) by Malcolm MacCoss and Thomas A. Baillie, Merck Research Laboratories, Rahway, N.J.
The present invention describes novel effects of orotate salts of pharmaceutical agents including CAI, on oral bioavailability of the agent. We have now, surprisingly found that oral administration of orotate salts of pharmaceutical agents, for example, CAI orotate, increases the bioavailability of charged CAI compared with the administration directly of the chemical equivalent of CAI. The CAI orotate salt has a better absorption profile which may be related to less side effects such as symptoms of emesis recorded, compared with CAI. These effects are expected to apply to other orotate salts of pharmaceutical agents in use.
The present invention also demonstrates the advantage of administering a drug as an orotate salt on reducing the drug's toxicity. The orotate salts of pharmaceutical agents have better clearance, that is, the fraction of the drug escaping first pass metabolism is increased thus reducing the potential for hepatic toxicity. Therefore, the higher and more consistent bioavailability of a drug when administered as orotate salt of drug orally and/or intravenously, improves the effectiveness and also attenuates the potential effects of any drug side effects and interactions. Medicinal chemists and organic chemists have heretofore, overlooked the unique design of drugs of the present invention.